Abstract
Trypanosoma cruzi infection is characterized by chronic parasitism of non-lymphoid tissues and is rarely eliminated despite potent adaptive immune responses. This failure to cure has frequently been attributed to a loss or impairment of anti-T. cruzi T cell responses over time, analogous to the T cell dysfunction described for other persistent infections. In this study, we have evaluated the role of CD8+ T cells during chronic T. cruzi infection (>100 dpi), with a focus on sites of pathogen persistence. Consistent with repetitive antigen exposure during chronic infection, parasite-specific CD8+ T cells from multiple organs expressed high levels of KLRG1, but exhibit a preferential accumulation of CD69+ cells in skeletal muscle, indicating recent antigen encounter in a niche for T. cruzi persistence. A significant proportion of CD8+ T cells in the muscle also produced IFNγ, TNFα and granzyme B in situ, an indication of their detection of and functional response to T. cruzi in vivo. CD8+ T cell function was crucial for the control of parasite burden during chronic infection as exacerbation of parasite load was observed upon depletion of this population. Attempts to improve T cell function by blocking PD-1 or IL-10, potential negative regulators of T cells, failed to increase IFNγ and TNFα production or to enhance T. cruzi clearance. These results highlight the capacity of the CD8+ T cell population to retain essential in vivo function despite chronic antigen stimulation and support a model in which CD8+ T cell dysfunction plays a negligible role in the ability of Trypanosoma cruzi to persist in mice.
Highlights
Chagas disease, caused by the protozoal parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis globally and affects at least 10 million individuals worldwide [1, 2]
The parasite Trypanosoma cruzi establishes lifelong infections in humans and other mammals, leading to severe cardiac and gastrointestinal complications known as Chagas disease
The factors that enable T. cruzi persistence remain undefined, in this and many other infection models, pathogen persistence has been attributed to the exhaustion of the immune system, of CD8+ T cells
Summary
Chagas disease, caused by the protozoal parasite Trypanosoma cruzi, is the leading cause of infectious myocarditis globally and affects at least 10 million individuals worldwide [1, 2]. During infections where complete pathogen clearance does not occur, or is significantly delayed, persistent antigen can drive the emergence of ‘exhausted’ T cells with diminished capacity to produce key cytokines and reduced replicative potential, and in extreme cases, T cell deletion by apoptosis [6,7,8]. In some instances, this exhausted state is reversible by interrupting one or more of a number of regulatory mechanisms responsible for restraining CD8+ T cell activity, e.g. regulatory T cells (Tregs), inhibitory cytokines, or inhibitory receptors such as programmed cell death-1 (PD-1) [9]. While these regulatory programs minimize immunopathology, they may compromise infection resolution [10,11,12,13]
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